tbuckley/cabot-search huggingface dataset:
Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS)
Authors: Esther Natalie Oliva, Marta Riva, Pasquale Niscola, Valeria Santini, Massimo Breccia, Valentina Giai, Antonella Poloni, Andrea Patriarca, Elena Crisà, Isabella Capodanno, Prassede Salutari, Gianluigi Reda, Nicola Cascavilla, Dario Ferrero, Attilio Guarini, Giovanni Tripepi, Giuseppe Iannì, Emilio Russo, Andrea Castelli, Bruno Fattizzo, Germana Beltrami, Monica Bocchia, Alfredo Molteni, Pierre Fenaux, Ulrich Germing, Alessandra Ricco, Giuseppe A. Palumbo, Stefana Impera, Nicola Di Renzo, Flavia Rivellini, Francesco Buccisano, Aspasia Stamatoullas-Bastard, Anna Marina Liberati, Anna Candoni, Ilaria Maria Delfino, Maria Teresa Arcadi, Patrizia Cufari, Lorenzo Rizzo, Irene Bova, Maria Grazia D'Errigo, Gina Zini, Roberto Latagliata
Journal: Journal of Clinical Oncology (2023)

In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia.In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 103/mm3) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 103/mm3 or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics.From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ2 = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times.Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.
BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis
Authors: Anja Schmitt, Melanie Grimm, Nina Kreienkamp, Hannah Junge, Jan Labisch, Laurentz Schuhknecht, Caroline Schönfeld, Elsa Görsch, Alessia Tibello, Kerstin Menck, Annalen Bleckmann, Claudia Lengerke, Frank Rosenbauer, Michael Grau, Mattia Zampieri, Klaus Schulze-Osthoff, Pavel Klener, Alexandra Dolnikova, Georg Lenz, Stephan Hailfinger
Journal: Blood (2023)
Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction
Authors: Saskia Bos, Pauline Pradère, Hanne Beeckmans, Andrea Zajacova, Bart M. Vanaudenaerde, Andrew J. Fisher, Robin Vos
Journal: Pharmacological Reviews (2023)

Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplantation and limited therapeutic options are available to slow the progressive decline in lung function. Most interventions are only temporarily effective in stabilising the loss of or modestly improving lung function, with disease progression resuming over time in the majority of patients. Therefore, identification of effective treatments that prevent the onset or halt progression of CLAD is urgently needed. As a key effector cell in its pathophysiology, lymphocytes have been considered a therapeutic target in CLAD. The aim of this review is to evaluate the use and efficacy of lymphocyte depleting and immunomodulating therapies in progressive CLAD beyond usual maintenance immunosuppressive strategies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation and extracorporeal photopheresis, and to explore possible future strategies. When considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for progressive CLAD patients. <b>Significance Statement</b> Effective treatments to prevent the onset and progression of chronic lung rejection after lung transplantation are still a major shortcoming. Based on existing data to date, considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation are currently the most viable second-line treatment options. Although important to note that interpretation of most results is hampered by the lack of randomised controlled trials.
Abstract 4009: Discovery of PLM-102, a highly potent 3rd generation FLT3 inhibitor, in drug-resistant FLT3-ITD-TKD mutated acute myeloid leukemia
Authors: Jin-Hee Park, Jae-Seon Lee, Su-jin Oh, So-Deok Lee, Yong June Choi, Keon Wook Kang, Miran Moon, Soo Yeon Jang, Myung Jin Kim, Yong-Chul Kim
Journal: Cancer Research (2023)

Abstract Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 25 ~ 30% of all acute myeloid leukemia (AML) cases and FLT3-ITD mutations are associated with a particularly unfavorable prognosis, with an increased risk of relapse and shorter overall survival (OS) compared with AML patients without the mutation. Even though multiple FLT3 inhibitors are in various stages of clinical evaluation, resistance to FLT3 inhibitors resulting from acquired point mutations in tyrosine kinase domain (TKD) have limited the sustained efficacy of treatments. Among them, a “gatekeeper” mutation (F691L) is resistant to most available FLT3 inhibitors. Here, we show the efficacy and mechanism of PLM-102, developed an orally available and highly selective small molecule, in overcoming drug-resistant FLT3-ITD-TKD mutations as a strong candidate of the 3rd generation of FLT3 inhibitor. PLM-102 displays extraordinary potency of enzyme inhibitory activities of all FLT3 WT/mutants including F691L with IC50 values of &amp;lt;1 nM. In FLT3-ITD-positive cell lines (MV4-11, MOLM-13, MOLM-14, Ba/F3-ITD-D835Y, Ba/F3-ITD-F691L), PLM-102 shows about 18~25-fold higher anti-proliferative activities than Gilteritinib. Also, PLM-102 potently inhibited the phosphorylation of FLT3 and its downstream signaling pathways, and induced apoptosis as evidenced by PARP-cleavage and caspase-3 activation. Moreover, in AML-related xenograft mouse models (MV4-11, MOLM-14, Ba/F3-ITD-D835Y, Ba/F3-ITD-F691L), once-daily oral dose of PLM-102 significantly suppressed the tumor growth and achieved complete tumor regression. In addition, the outstanding efficacy of our compound has been confirmed in large tumor xenograft models. These results are very encouraging because large tumors have a limited blood supply and high interstitial fluid pressure, leading to a poor absorption of anticancer drugs. Pharmacokinetics of PLM-102 displayed higher bone-marrow exposure indicating better target engagement and benefits in the clinical translation in AML. In conclusion, PLM-102 is a promising therapeutic candidate for the FLT3-ITD-mutated AML as well as the acquired resistance to current FLT3 inhibitors. Citation Format: Jin-Hee Park, Jae-Seon Lee, Su-jin Oh, So-Deok Lee, Yong June Choi, Keon Wook Kang, Miran Moon, Soo Yeon Jang, Myung Jin Kim, Yong-Chul Kim. Discovery of PLM-102, a highly potent 3rd generation FLT3 inhibitor, in drug-resistant FLT3-ITD-TKD mutated acute myeloid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4009.
Rapid recruitment and IFN-I–mediated activation of monocytes dictate focal radiotherapy efficacy
Authors: Sirimuvva Tadepalli, Derek R. Clements, Sanjana Saravanan, Rebeca Arroyo Hornero, Anja Lüdtke, Beau Blackmore, Joao A. Paulo, Andres Gottfried-Blackmore, David Seong, Soyoon Park, Leslie Chan, Benjamin J. Kopecky, Zhaoyuan Liu, Florent Ginhoux, Kory J. Lavine, John Patrick Murphy, Matthias Mack, Edward E. Graves, Juliana Idoyaga
Journal: Science Immunology (2023)

The recruitment of monocytes and their differentiation into immunosuppressive cells is associated with the low efficacy of preclinical nonconformal radiotherapy (RT) for tumors. However, nonconformal RT (non-CRT) does not mimic clinical practice, and little is known about the role of monocytes after RT modes used in patients, such as conformal RT (CRT). Here, we investigated the acute immune response induced by after CRT. Contrary to non-CRT approaches, we found that CRT induces a rapid and robust recruitment of monocytes to the tumor that minimally differentiate into tumor-associated macrophages or dendritic cells but instead up-regulate major histocompatibility complex II and costimulatory molecules. We found that these large numbers of infiltrating monocytes are responsible for activating effector polyfunctional CD8
Abstract 1082: Effect of doublet treatment versus single-agent treatment in gastric cancers with/without <i>MET</i> amplification or a <i>MET</i> exon 14 skipping mutation
Authors: Dae Young Zang, sung-hwa sohn, Hee Jung Sul, Bum Jun Kim
Journal: Cancer Research (2023)

Abstract Although conventional combination chemotherapy for advanced gastric cancer (GC) is associated with increased survival, it has major adverse effects, which necessitate the development of more effective, less toxic treatments. Combinations of multiple anti-cancer drugs, such as paclitaxel plus ramucirumab, have recently been used for the second-line treatment of advanced GC. This study evaluated the MET copy number variation (CNV), mutations, and gene and protein expression in human GC cells and the differential susceptibility of GC cells to single (tepotinib, ramucirumab, or paclitaxel) or doublet (tepotinib plus paclitaxel or ramucirumab plus paclitaxel) regimens. Compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibited the growth of GC cells with a MET exon 14 skipping mutation and those without MET amplification but with phosphorylated MET in a dose-dependent manner with a concomitant induction of cell death. Tepotinib plus paclitaxel and ramucirumab plus paclitaxel similarly inhibited the growth of GC cells without a MET amplification or MET phosphorylation in a dose-dependent manner without inducing cell death. However, tepotinib alone or tepotinib plus ramucirumab was more effective in c-MET-positive GC cells (CNV &amp;gt; 30) than ramucirumab alone, paclitaxel alone, or ramucirumab plus paclitaxel. Our in vitro findings suggest that, compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibits the growth of c-MET-positive GC cells, GC cells without a MET amplification but with phosphorylated MET, and those with MET mutations. Tepotinib alone was as effective as tepotinib plus paclitaxel in c-MET-positive GC cells. Clinical studies are required to confirm the therapeutic effects of these regimens. Citation Format: Dae Young Zang, sung-hwa sohn, Hee Jung Sul, Bum Jun Kim. Effect of doublet treatment versus single-agent treatment in gastric cancers with/without MET amplification or a MET exon 14 skipping mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1082.
Abstract 111: Characterizing subpopulation response to doxorubicin in a barcode-labeled triple negative breast carcinoma cell line
Authors: Daylin Morgan, Amy Brock
Journal: Cancer Research (2023)

Abstract Despite recent advances in diagnosis and late-stage treatment, progression-free survival is not achieved for many cancer patients. Triple negative breast cancer (TNBC) poses a particular challenge as an aggressive and heterogeneous disease lacking the benefit of hormonal therapies. We have utilized a novel genetic lineage-tracking system, ClonMapper in TNBC cells to elucidate the pre-existent and de novo cell states that arise from chemotherapeutic intervention. ClonMapper genetic tags were stably integrated into MDA-MB-231 cells using lentiviral transduction and positively labeled cells were isolated with fluorescence-activated cell sorting to generate a starting library of ~500 uniquely barcoded cells. Barcode-labeled MDA-MB-231 were selected with doxorubicin at 250, 400 and 550 nM for 48 hours and allowed to recover. To determine the contribution of transcriptomic state to cellular drug response we carried out single cell RNA-sequencing (scRNA-seq) on 4 populations: a pretreatment cell library, an intermediary taken 30 h into drug selection, and two recovered populations from the 250 nM group. Importantly, we are able to capture and deconvolve ClonMapper lineage tags from scRNA-seq results and overlay them with transcriptomic state. Following treatment with doxorubicin we found a dose-dependent reduction in the number of unique lineages, with all replicates showing &amp;gt;6-fold decrease. Post-treatment replicates were each significantly comprised (90%) by fewer than three individual lineages. Lineage-resolved transcriptomics revealed two distinct lineage-specific subpopulations within the pretreatment cell library. These subpopulations demonstrated unique survivorship trajectories, beginning 30 h into selection and remaining well-separated following recovery from treatment. Comparing these subpopulations directly we observe enrichment for several pathways with markers genes remaining highly expressed post-treatment. Crucially, both subpopulations harbor a unique set of lineages which are found to survive treatment. However, in the absence of treatment we find that one subpopulation displays a faster growth rate and is likely to outcompete the other in culture conditions. The more proliferative subpopulation is marked by enrichment of Myc targets, compared with enrichment of glycolysis and KRAS signaling in the less proliferative subpopulation. This data demonstrates that subclonal heterogeneity inherent within this TNBC cell model, drives differential cell responses to chemotherapy. Citation Format: Daylin Morgan, Amy Brock. Characterizing subpopulation response to doxorubicin in a barcode-labeled triple negative breast carcinoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 111.
Abstract 4656: Targeting macrophage PI3KGamma in aggressive prostate cancer
Authors: Kenneth M. Adusei, Thomas R. Nirschl, Alex J.-E. Lee, Fan Shen, Xiaoxu Wang, Jade Alvarez, Tamara L. Lotan, Judith Varner, Jelani Zarif
Journal: Cancer Research (2023)

Abstract The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family of lipid kinases play key roles in cancer biology by promoting cell motility, growth, and survival. Of the four class I PI3K isoforms, PI3Kα,β,δ,γ, the PI3Kγ isoform is primarily expressed by myeloid cells. Studies from the Varner lab have established that the macrophage lipid kinase, PI3Kγ, selectively promotes myeloid cell trafficking and immune suppressive transcription in tumor associated monocytes and macrophages, thereby inhibiting T cell recruitment, activation, and tumor eradication. We hypothesized that antagonism or deletion of PI3Kγ would induce tumor growth inhibition in vivo in prostate cancer (PCa) models. To test our hypothesis, we implanted syngeneic murine prostate cancer tumors (B6CaP) into global PI3Kγ knock out mice and preliminary studies show severe tumor growth inhibition. Using a publicly available single cell RNA sequencing database of metastatic PCa (mPCa) tumors from bone, we calculated regulon scores for transcription factors C/EBPβ and NFκB which are up and down-regulated by PI3Kγ signaling in myeloid cells respectively. This analysis indicated that a notable proportion of monocytes in mPCa have active PI3Kγ signaling based on C/EBPβ activity and a lack of NFκB activity. Finally, we tested the significance of eganelisib treatment on monocytes and found that this pathway was essential for monocyte survival during macrophage differentiation and adhesion. Altogether, our proposed research delineates the mechanistic roles of PI3Kγ in the regulation of prostate cancer tumor growth and support PI3Kγ as a target to sensitize PCa to immune checkpoint inhibitors. Citation Format: Kenneth M. Adusei, Thomas R. Nirschl, Alex J.-E. Lee, Fan Shen, Xiaoxu Wang, Jade Alvarez, Tamara L. Lotan, Judith Varner, Jelani Zarif. Targeting macrophage PI3KGamma in aggressive prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4656.
Abstract 5552: MAGE-A3 and MAGE-A4 protein show co-expression in tumor of lung, bladder, and colon cancer
Authors: Rachel Gonzalez
Journal: Cancer Research (2023)

Abstract Melanoma Antigen Gene Family (MAGE-A) are part of the cancer-testis antigens whose limited expression in normal tissues and high expression in cancer make them excellent targets for immunotherapy. Clinical trials have already begun targeting MAGE-A3 and MAGE-A4 proteins in tumors. Should these trials lead to new treatment protocols, it is important to develop a diagnostic immunohistochemistry (IHC) tool for pre-screening patients who would benefit. The MAGE-A family consists of 12 members that share up to 85% sequence homology presenting a challenge for finding highly specific antibodies for IHC. Using CytoSections, a new screening control tool for IHC, ICC, IF, and in-situ hybridization, highly specific IHC MAGE-A3 and MAGE-A4 antibodies were developed and screened. The MAGE-A3 and MAGE-A4 antibodies were assessed on twenty-two lung cancers, twenty-one colon cancer, and more than thirty bladder cancers which resulted in cases that co-express MAGE-A3 and MAGE-A4 proteins in all three types of tumors. Using immunofluorescence, tumors positive for both proteins were double stained for MAGE-A3 and MAGE-A4 to show the proteins were co-expressed in the same tumor cells. Immunohistochemistry continues to be a rapid and reproducible method for the detection of proteins in tumors. Antibodies specific to MAGE-A3 and A4 proteins for IHC may be a useful tool in predicting outcomes or benefits for patients. Citation Format: Rachel Gonzalez. MAGE-A3 and MAGE-A4 protein show co-expression in tumor of lung, bladder, and colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5552.
Abstract 56: Unlocking primary cell culture for more relevant in vitro models
Authors: Benjamin Theek, Anne Franke, David Agorku, Katharina Lamfried, Nojan Jelveh, Michael Linnebacher, Lilian Martinez Carrera, Olaf Hardt
Journal: Cancer Research (2023)

Abstract Tumor cell lines are commonly used to investigate biological and translational questions. However, many cell lines have been cultured in serum-containing medium for decades, continuously accumulating genetic and epigenetic aberrations. Without a doubt, these cell lines have very little in common with the tumor they originate from, resulting in low biological and clinical relevance. Despite these drawbacks, cell lines are still the most frequent research tool when it comes to the use of ex vivo models. Yet, in light of higher consistency, reproducibility, and biological relevance, more and more researchers are paying attention to which cells and culture medium to use. Although primary cell cultures certainly reflect cellular and genetic heterogeneity of the original tumor, finding a suitable medium that supports their growth and maintains genetic heterogeneity remains challenging. To this end, we developed serum-free cell culture media to cultivate primary epithelial tumor cells of pancreatic, renal, and ovarian origin. Notably, generating in vitro models with high biological relevance was successful when using our media during the derivation and expansion of tumor cell lines from primary and xenotransplanted tumors. Here, we present another serum-free cell culture media supporting the in vitro growth of primary colon adenocarcinoma. Using this optimized medium, we had a 42% success rate in establishing a primary cell culture for a given tumor sample, higher than for any other media tested in our hands. Next to 2D cell culture, our formulation supports 3D tumoroid formation when cells are embedded in a basement membrane matrix. Furthermore, targeted sequencing of 486 tumor-associated genes revealed that more than 99% of the detected genetic variants in an early passage (p11) were also present after extended time in culture (p53). In summary, our new serum-free medium enables the efficient derivation and expansion of primary tumor and xenograft-derived colon adenocarcinoma cell cultures in 2D and 3D, yet retaining their genetic identity. Citation Format: Benjamin Theek, Anne Franke, David Agorku, Katharina Lamfried, Nojan Jelveh, Michael Linnebacher, Lilian Martinez Carrera, Olaf Hardt. Unlocking primary cell culture for more relevant in vitro models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 56.